Procedure-related risk of miscarriage following chorionic villus sampling and amniocentesis

Objective: The objective of our study was to estimate the procedure-related risks of miscarriage following CVS and amniocentesis in a large unselected screened and to determine whether these risks are consistent with those reported in systematic reviews and meta-analysis. Methods: This was a retrospective cohort study undertaken at a large Fetal Medicine Unit in the United Kingdom during the period of January 2009 to May 2018. We included all singleton pregnancies that booked at our unit before 20 weeks after excluding those with multiple pregnancies, major fetal defects, terminations and lost to follow-up. We estimated the risk of miscarriage in those that had a CVS or amniocentesis as well as those that did not have any invasive procedure, to estimate the procedure-related risk as a risk-difference (95% confidence interval [CI]). Univariate and multivariate regression analysis was used to derive odds ratios (OR) (95%CI) and determine which maternal and pregnancy characteristics provided a significant contribution in prediction of miscarriage and whether CVS or amniocentesis provided a significant independent. Results: During the study period, there were 45,120 singleton pregnancies, including 1,546 that had an invasive procedure. We excluded 1,429 pregnancies (3.2%), due to fetal defects, termination of pregnancy or those with missing outcomes. In pregnancies that underwent CVS, the risk of miscarriage was 1.5% (13/861), compared to 1.2% (476/39,152) in pregnancies that did not have a procedure (p=0.437). In pregnancies that underwent an amniocentesis, the risk of miscarriage was 0.8% (3/375), compared to 1.2% (491/42,463) in those that did not (p=0.520). Univariate and multivariate regression analysis demonstrated that there was no significant prediction to the risk of miscarriage from CVS (p=0.399; p=0.592, respectively) or amniocentesis (p=0.543; p=0.550, respectively). The risk of procedure-related loss attributed to CVS was 0.29% (95%CI: -0.53-1.12) and that following amniocentesis was -0.36% (95%CI: -1.26-0.55), which was not significantly different from those that did not have any procedure. Conclusion: The procedure-related risks of miscarriage following CVS and amniocentesis are considerably lower than currently quoted. The estimates of risks based on our study are 0.29% for CVS and -0.36 for amniocentesis

Bayesian multi-objective optimisation with mixed analytical and black-box functions: application to tissue engineering

Tissue engineering and regenerative medicine looks at improving or restoring biological tissue function in humans and animals. We consider optimising neotissue growth in a three-dimensional scaffold during dynamic perfusion bioreactor culture, in the context of bone tissue engineering. The goal is to choose design variables that optimise two conflicting objectives: (i) maximising neotissue growth and (ii) minimising operating cost. We make novel extensions to Bayesian multi-objective optimisation in the case of one analytical objective function and one black-box, i.e. simulation-based, objective function. The analytical objective represents operating cost while the black-box neotissue growth objective comes from simulating a system of partial differential equations. The resulting multi-objective optimisation method determines the trade-off in the variables between neotissue growth and operating cost. Our method outperforms the most common approach in literature, genetic algorithms, in terms of data efficiency, on both the tissue engineering example and standard test functions. The resulting method is highly applicable to real-world problems combining black-box models with easy-to-quantify objectives like cost

Prevention of stillbirths: impact of a two-stage screening for vasa previa

Objectives: To examine the feasibility and effectiveness of a two-stage ultrasound screening strategy for detection of vasa previa and estimate the potential impact of screening on prevention of stillbirth. Methods: This was a retrospective examination of data from prospective screening for vasa previa in singleton pregnancies undertaken at the Fetal Medicine Centre at Medway Maritime Hospital, UK between 2012 and 2018. Women booked for prenatal care and delivery in our hospital had routine ultrasound examinations at 11-13 and 20-22 weeks’ gestation. Those with velamentous cord insertion at the inferior part of the placenta at the first-trimester scan and those with low-lying placenta at the second-trimester scan were classified as high-risk for vasa previa and had transvaginal sonography specifically searching for vasa previa at the time of the 20-22 weeks scan. The management and outcome of cases with suspected vasa previa is described. We excluded cases of miscarriage or termination at <24 weeks’ gestation. Results: The study population of 26,830 singleton pregnancies, included 21 (0.08% or 1 in 1,278) with vasa previa. In all cases of vasa previa the diagnosis was made at the 20-22 weeks scan and confirmed by gross and histological examination of the placenta postnatally. At the 11-13 weeks scan the cord insertion was classified as central in 25,071 (93.4%) cases, marginal in 1,680 (6.3%), and velamentous in 79 (0.3%). In 16 (76.2%) of the 21 cases of vasa previa, the cord insertion at the first-trimester scan was classified as velamentous at the inferior part of the placenta, in 2 (9.5%) as marginal and in 3 (14.3%) as central. The 21 cases of vasa previa were managed on an outpatient basis with serial scans for measurement of cervical length and elective cesarean section at 34 weeks’ gestation; all babies were liveborn but there was one neonatal death. In the study population there were 83 stillbirths and postnatal examination showed no evidence of vasa previa in any of the cases. On the assumption that if we had not diagnosed prenatally all 21 cases of vasa previa in our population half of these cases would have resulted in stillbirth, then the potential impact of screening is prevention of 9.6% (10/104) of stillbirths. Conclusion: A two-stage strategy of screening for vasa previa can be incorporated into routine clinical practice and such strategy could potentially reduce the rate of stillbirth

Mapping the use of computational modelling and simulation in clinics: A survey

In silico medicine describes the application of computational modelling and simulation (CM&S) to the study, diagnosis, treatment or prevention of a disease. Tremendous research advances have been achieved to facilitate the use of CM&S in clinical applications. Nevertheless, the uptake of CM&S in clinical practice is not always timely and accurately reflected in the literature. A clear view on the current awareness, actual usage and opinions from the clinicians is needed to identify barriers and opportunities for the future of in silico medicine. The aim of this study was capturing the state of CM&S in clinics by means of a survey toward the clinical community. Responses were collected online using the Virtual Physiological Human institute communication channels, engagement with clinical societies, hospitals and individual contacts, between 2020 and 2021. Statistical analyses were done with R. Participants (n = 163) responded from all over the world. Clinicians were mostly aged between 35 and 64 years-old, with heterogeneous levels of experience and areas of expertise (i.e., 48% cardiology, 13% musculoskeletal, 8% general surgery, 5% paediatrics). The CM&S terms “Personalised medicine” and “Patient-specific modelling” were the most well-known within the respondents. “In silico clinical trials” and “Digital Twin” were the least known. The familiarity with different methods depended on the medical specialty. CM&S was used in clinics mostly to plan interventions. To date, the usage frequency is still scarce. A well-recognized benefit associated to CM&S is the increased trust in planning procedures. Overall, the recorded level of trust for CM&S is high and not proportional to awareness level. The main barriers appear to be access to computing resources, perception that CM&S is slow. Importantly, clinicians see a role for CM&S expertise in their team in the future. This survey offers a snapshot of the current situation of CM&S in clinics. Although the sample size and representativity could be increased, the results provide the community with actionable data to build a responsible strategy for accelerating a positive uptake of in silico medicine. New iterations and follow-up activities will track the evolution of responses over time and contribute to strengthen the engagement with the medical community

Occurrence and Treatment of Bone Atrophic Non-Unions Investigated by an Integrative Approach

Recently developed atrophic non-union models are a good representation of the clinical situation in which many nonunions develop. Based on previous experimental studies with these atrophic non-union models, it was hypothesized that in order to obtain successful fracture healing, blood vessels, growth factors, and (proliferative) precursor cells all need to be present in the callus at the same time. This study uses a combined in vivo-in silico approach to investigate these different aspects (vasculature, growth factors, cell proliferation). The mathematical model, initially developed for the study of normal fracture healing, is able to capture essential aspects of the in vivo atrophic non-union model despite a number of deviations that are mainly due to simplifications in the in silico model. The mathematical model is subsequently used to test possible treatment strategies for atrophic non-unions (i.e. cell transplant at post-osteotomy, week 3). Preliminary in vivo experiments corroborate the numerical predictions. Finally, the mathematical model is applied to explain experimental observations and identify potentially crucial steps in the treatments and can thereby be used to optimize experimental and clinical studies in this area. This study demonstrates the potential of the combined in silico-in vivo approach and its clinical implications for the early treatment of patients with problematic fractures

Toward a Regulatory Pathway for the Use of in Silico Trials in The Ce Marking of Medical Devices

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing

Ideas and perspectives : Tracing terrestrial ecosystem water fluxes using hydrogen and oxygen stable isotopes – challenges and opportunities from an interdisciplinary perspective

The authors thank Marialaura Bancheri, Michele Bottazzi, Roman Cibulka, Massimo Esposito, Alba Gallo, Cesar D. Jimenez-Rodriguez, Angelika Kuebert, Ruth Magh, Stefania Mambelli, Alessia Nannoni, Paolo Nasta, Vladimir Rosko, Andrea Rücker, Noelia Saavedra Berlanga, Martin Šanda, and Anna Scaini for their contributions during the discussion at the workshop “Isotope-based studies of water partitioning and plant–soil interactions in forested and agricultural environments”. The authors also thank “Villa Montepaldi” and the University of Florence for the access to the workshop location, and the municipality of San Casciano in Val di Pesa for logistical support. The authors thank the Department of Innovation, Research and University of the Autonomous Province of Bozen/Bolzano for covering the Open Access publication costs. Last, but not least, the authors wish to thank Matthias Sprenger, Stephen Good, and J. Renée Brooks, as well as the Editor David R. Bowling, whose constructive reviews greatly improved this manuscript.Peer reviewedPublisher PD

Cartilaginous endplates: a comprehensive review on a neglected structure in intervertebral disc research

The cartilaginous endplates (CEP) are key components of the intervertebral disc (IVD) necessary for sustaining the nutrition of the disc while distributing mechanical loads and preventing the disc from bulging into the adjacent vertebral body. The size, shape, and composition of the CEP are essential in maintaining its function, and degeneration of the CEP is considered a contributor to early IVD degeneration. In addition, the CEP is implicated in Modic changes, which are often associated with low back pain. This review aims to tackle the current knowledge of the CEP regarding its structure, composition, permeability, and mechanical role in a healthy disc, how they change with degeneration, and how they connect to IVD degeneration and low back pain. Additionally, the authors suggest a standardized naming convention regarding the CEP and bony endplate and suggest avoiding the term vertebral endplate. Currently, there is limited data on the CEP itself as reported data is often a combination of CEP and bony endplate, or the CEP is considered as articular cartilage. However, it is clear the CEP is a unique tissue type that differs from articular cartilage, bony endplate, and other IVD tissues. Thus, future research should investigate the CEP separately to fully understand its role in healthy and degenerated IVDs. Further, most IVD regeneration therapies in development failed to address, or even considered the CEP, despite its key role in nutrition and mechanical stability within the IVD. Thus, the CEP should be considered and potentially targeted for future sustainable treatments

Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: building model credibility

The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk-informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk-based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick-start tool by regulators. Altogether, this white paper provides a practical approach to model evaluation, applicable in both scientific and regulatory evaluation contexts